Coated devices and method of making coated devices that reduce smooth muscle cell proliferation and platelet activity

ABSTRACT

The present invention relates generally to the maintenance of blow flood using drug eluting stents and/or other coated medical devices to increased length of time of blood flow. Further, the present invention relates to drug-releasing coated devices for reducing smooth muscle cell proliferation and platelet activity to further limit restenosis utilizing resveratrol and quercetin, polyphenols that are linked to the cardioprotection of red wine consumption. The present invention also provides products and methods for treating or preventing atherosclerosis, stenosis, restenosis, smooth muscle cell proliferation, platelet cell activation and other clotting mechanisms, occlusive disease, or other abnormal lumenal cellular proliferation condition in a location within the body of a patient.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation under 35 U.S.C. §111(a) ofInternational Application No. PCT/US2008/082440 filed on Nov. 5, 2008and published in English as WO/2009/061787 on May 14, 2009, which claimsthe benefit under 35 U.S.C. §119(e) of the filing date of U.S.provisional application Ser. No. 61/001,916 filed Nov. 5, 2007, thedisclosures of which applications and publications are incorporated byreference herein.

BACKGROUND OF THE INVENTION

The present invention relates generally to the maintenance of blow floodusing drug eluting stents and other medical devices to increase lengthof time of blood flow. Further, the present invention relates todrug-releasing stents and/or other coated medical devices for reducingsmooth muscle cell proliferation and platelet activity to further limitrestenosis utilizing resveratrol and quercetin, polyphenols that arelinked to the cardioprotection of red wine consumption. The presentinvention also provides products and methods for treating or preventingatherosclerosis, stenosis, restenosis, smooth muscle cell proliferation,platelet cell activation and other clotting mechanisms, occlusivedisease, or other abnormal lumenal cellular proliferation condition in alocation within the body of a patient.

DESCRIPTION OF RELATED ART

Atherosclerosis is a disease characterized by cholesterol-laden plaqueformation within the artery wall, leading to vessel narrowing and bloodflow reduction. Occlusion of certain key arteries can precipitate amajor cardiac event. In the United States, the prevalence rate ofatherosclerosis is predicted to be 1 in 58 or 1.70%. Furthermore,atherosclerosis is the first-listed diagnosis for 35 of every 10,000hospitalizations in the United States, or 0.35%. Over 70% of patientswith atherosclerosis receive some sort of treatment that involvescatheritization to correct the blockage. The first such treatment usingmechanical opening of the occluded areas relied solely on balloonangioplasty. In this procedure, an inflatable device is inserted throughan artery to the blockage via a catheter, at which point the balloon isinflated to create an opening in the stenotic area. One approach toclearing an artery that has been constricted or clogged due to stenosisis percutaneous transluminal coronary angioplasty (PTCA) or ballooncoronary angioplasty. In this procedure, a balloon catheter is insertedand expanded in the constricted portion of the vessel for clearing theblockage. About one-third of patients who undergo PTCA suffer fromrestenosis, the renarrowing of the widened segment, within about sixmonths of the procedure. Restenosed arteries may have to undergo anotherangioplasty.

The limitation of balloon angioplasty is that it is often only ashort-term solution, as both the balloon inflation and stretching of thevessel can denude the vessel wall of endothelium and impart endothelialinjury and dysfunction to the surrounding areas. Platelets, lymphocytesand monocytes are then recruited to the injured area. Release of basicfibroblast growth factor (bFGF) and platelet derived growth factor(PDGF) from platelets and dying vascular smooth muscle cells andendothelial cells promotes vascular smooth muscle cells to migrate fromthe underlying medial layer to the intima, where they beginproliferating. This vascular smooth muscle cell (VSMC) proliferativeresponse induces a re-narrowing of the lumen (or “restenosis”), onceagain restricting blood flow.

Balloon angioplasty has a restenosis rate of approximately 30% over 6months and a high rate of coronary artery dissection. The high failurerate of balloon angioplasty led to the use of bare metal stents toimprove blood flow. Bare metal stents have been used for the long termmaintenance of blow flood and prevention of restenosis. These stentsgenerally consist of expandable metal struts. They are delivered in anunexpanded form to the affected area via a catheter and inner balloon.Once at the site of injury, the balloon is inflated such that the stentis locked in an expanded state. The balloon is then deflated, and thecatheter and balloon are removed while the stent remains in place. Baremetal stents have a lowered rate of restenosis in some cases, butfailure has still varied between 10%-40%.

Stents are not 100% effective in preventing restenosis at the implantsite. Restenosis can occur over the length of the stent and/or past theends of the stent. Physicians have recently employed new types of stentsthat are coated with a thin polymer film loaded with a drug thatinhibits smooth cell proliferation. These drug-eluting stents (DES) wereconceived as a way of further limiting restenosis. In this technology, acoating of some chemical compound is placed on the stent in such amanner that it is released slowly over the course of several months.

The coating is applied to the stent prior to insertion into the arteryusing methods well known in the art, such as a solvent evaporationtechnique. The solvent evaporation technique entails mixing the polymerand drug in a solvent. The solution comprising polymer, drug, andsolvent can then be applied to the surface of the stent by eitherdipping or spraying. The stent is then subjected to a drying process,during which the solvent is evaporated, and the polymeric material, withthe drug dispersed therein, forms a thin film layer on the stent.

The release mechanism of the drug from the polymeric materials dependson the nature of the polymeric material and the drug to be incorporated.The drug diffuses through the polymer to the polymer-fluid interface andthen into the fluid. Release can also occur through degradation of thepolymeric material. The degradation of the polymeric material can occurthrough a number of mechanisms such as hydrolysis or enzymatic cleavage.The degradation can occur via surface erosion or simultaneouslythroughout the bulk of the polymer film. Degradation adds anotherdimension to the timing and control drug release profiles in addition todiffusion. In addition, polymer degradation insures that large polymerchains that might elicit foreign body reactions are not left behind.

An important consideration in using coated stents is the release rate ofthe drug from the coating. It is desirable that an effective therapeuticamount of the drug be released from the stent for the longest period oftime possible. Burst release, a high release rate immediately followingimplantation, is undesirable and a persistent problem. While typicallynot harmful to the patient, a burst release “wastes” the limited supplyof the drug by releasing several times the effective amount required andshortens the duration of the release period. Several techniques havebeen developed in an attempt to reduce burst release. For example, U.S.Pat. No. 6,258,121 to Yang et al. discloses a method of altering therelease rate by blending two polymers with differing release rates andincorporating them into a single layer.

Though this generation of DES holds promise, the currently approveddrugs have unfavorable side effects such as the inhibition the formationof a functional vascular endothelium. This can cause potentially lifethreatening late terms events. Thus, there remains a need for animproved system and method that increases blood flow through stenoticareas and reduces restenosis without side effects from the drugs coatingthe device. In view of the foregoing, the development of a device havinga coating of polymeric material with improved biologically active agentor agents dispersed therein would be a significant advance in the art.The current invention treats and/or prevents atherosclerosis, stenosis,restenosis, smooth muscle cell proliferation, platelet cell activationand other clotting mechanisms, occlusive disease, or other abnormallumenal cellular proliferation condition in a location within the bodyof a patient, and can be effective in delivering a wide range of othertherapeutic agents to the implant site over a relatively extended periodof time.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY OF THE INVENTION

The invention provides a drug eluting intravascular stent comprising:(a) a generally cylindrical stent body; (b) an adherent layer on thestent comprising a composite of polymer and a first active agentselected from the group consisting of resveratrol, pharmaceuticallyacceptable salts, and pharmaceutically acceptable derivatives thereof,and an optional second active agent selected from the group consistingof quercetin, pharmaceutically acceptable salts, and pharmaceuticallyacceptable derivatives thereof, dispersed within the polymer. Theinvention further provides a stent wherein the stent body has a metalsurface. The invention further provides a stent wherein the stent bodyis micro- or nanoporous. The invention further provides a stent whereinthe stent body has a polymeric surface. The invention further provides astent wherein the polymer is a bioabsorbable polymer. The inventionfurther provides a stent wherein the polymer is a biostable polymer. Theinvention further provides a stent wherein the first and second activeagents are in a ratio which is selected from the group consisting ofabout 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4,about 4:1, about 1:5, about 5:1, about 1:10, about 10:1, about 1:20,about 20:1, about 1:25, about 25:1, about 1:50, about 50:1, about 1:100,about 100:1, about 1:200, about 200:1, about 1:250, about 250:1, about1:500, and about 500:1 by weight percent. The invention further providesa stent wherein the first and second active agents are in a ratio whichis selected from the group consisting of about 1:5, about 1:2, and about1:1 by weight percent.

The invention provides a drug eluting intravascular stent comprising:(a) a generally cylindrical stent body; (b) an adherent layer on thestent comprising a composite of polymer and at least one active agentdispersed within the polymer, wherein the at least one active agent isselected from the group consisting of resveratrol, pharmaceuticallyacceptable salts of resveratrol, pharmaceutically acceptable derivativesof resveratrol, quercetin, pharmaceutically acceptable salts ofquercetin, pharmaceutically acceptable derivatives of quercetin,combinations thereof, and mixtures thereof. The invention furtherprovides a stent wherein the coating is a polymer selected from thegroup consisting of polystyrene-polyisobutylene block copolymers,polyethylene terephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof. The invention further provides astent wherein the first and second active agents and polymer are in aratio selected from the group consisting of about 1:1, about 1:2, about2:1, about 1:2.5, about 2.5:1, about 1:4, about 4:1, about 1:5, about5:1, about 1:10, about 10:1, about 1:20, about 20:1, about 1:25, about25:1, about 1:50, about 50:1, about 1:100, about 100:1, about 1:200,about 200:1, about 1:250, about 250:1, about 1:500, and about 500:1 byweight percent. The invention further provides a stent wherein thecomposite includes a plurality of layers. The invention further providesa stent wherein the ratio of pharmaceutically active agents to polymeris varied in some of the layers. The invention further provides a stentwherein the biologically active agent is selected from agents whichtreat or prevent atherosclerosis, stenosis, restenosis, smooth musclecell proliferation, platelet cell activation and other clottingmechanisms, occlusive disease, or other abnormal lumenal cellularproliferation condition within a body of a patient. The inventionfurther provides a stent wherein the concentration of the first activeagent based on the surface area of the stent ranges from about 1 toabout 5 μg/mm2, and the concentration of the optional second activeagent based on the surface area of the stent ranges from about 1 toabout 5 μg/mm2. The invention further provides a stent, wherein each ofthe active agents may have different release profiles. The inventionfurther provides a stent wherein the release profile of the activeagents may be selected between rapid and delayed. The invention furtherprovides a stent wherein a rapid profile coating releases an activeagent substantially within one to a few hours. The invention furtherprovides a stent wherein a delayed profile coating releases an activeagent and/or agents over a period of at least one month, at least twomonths, at least six months, or at least one year.

The invention provides the use of a drug eluting intravascular stentcomprising: (a) a generally cylindrical stent body; and (b) an adherentlayer on the stent comprising a composite of polymer and a first activeagent selected from the group consisting of resveratrol,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, and an optional second active agent selected fromthe group consisting of quercetin, pharmaceutically acceptable salts,and pharmaceutically acceptable derivatives thereof, dispersed withinthe polymer in the manufacture of a medicament for the treatment orprevention of atherosclerosis, stenosis, restenosis, smooth muscle cellproliferation, platelet cell activation and other clotting mechanisms,occlusive disease, or other abnormal lumenal cellular proliferationcondition in a location within the body of a patient.

The invention further provides a drug eluting intravascular stentcomprising: (a) a generally cylindrical stent body; and (b) an adherentlayer on the stent comprising a composite of polymer and a first activeagent selected from the group consisting of resveratrol,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, and an optional second active agent selected fromthe group consisting of quercetin, pharmaceutically acceptable salts,and pharmaceutically acceptable derivatives thereof, dispersed withinthe polymer for use in the treatment or prevention of atherosclerosis,stenosis, restenosis, smooth muscle cell proliferation, platelet cellactivation and other clotting mechanisms, occlusive disease, or otherabnormal lumenal cellular proliferation condition in a location withinthe body of a patient.

The invention provides a method for treating or preventingatherosclerosis, stenosis, restenosis, smooth muscle cell proliferation,platelet cell activation and other clotting mechanisms, occlusivedisease, or other abnormal lumenal cellular proliferation condition in alocation within the body of a patient, comprising: implanting a drugeluting intravascular stent comprising: (a) a generally cylindricalstent body; and (b) an adherent layer on the stent comprising acomposite of polymer and a first active agent selected from the groupconsisting of resveratrol, pharmaceutically acceptable salts, andpharmaceutically acceptable derivatives thereof, and an optional secondactive agent selected from the group consisting of quercetin,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, dispersed within the polymer; further wherein thepharmaceutically active agent is locally delivered at the location in amanner that is adapted to substantially treat or prevent theatherosclerosis, stenosis, restenosis, smooth muscle cell proliferation,platelet cell activation and other clotting mechanisms, occlusivedisease, or other abnormal lumenal cellular proliferation condition inthe patient. The invention further provides a method wherein the polymeris selected from polystyrene-polyisobutylene block copolymers,polyethylene terephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof. The invention further provides amethod wherein the ratio of first to second active agents is in a rangeselected from the group consisting of about 1:1, about 1:2, about 2:1,about 1:2.5, about 2.5:1, about 1:4, about 4:1, about 1:5, about 5:1,about 1:10, about 10:1, about 1:20, about 20:1, about 1:25, about 25:1,about 1:50, about 50:1, about 1:100, about 100:1, about 1:200, about200:1, about 1:250, about 250:1, about 1:500, and about 500:1 by weightpercent. The invention further provides a method wherein, wherein theratio of first to second active agents is in the range selected from thegroup consisting of about 1:5, about 1:2, and about 1:1 resveratrol toquercetin by weight percent. The invention further provides a methodwherein, wherein the ratio of the first and second active agents topolymer is in a range selected from the group consisting of about 1:1,about 1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4, about 4:1,about 1:5, about 5:1, about 1:10, about 10:1, about 1:20, about 20:1,about 1:25, about 25:1, about 1:50, about 50:1, about 1:100, about100:1, about 1:200, about 200:1, about 1:250, about 250:1, about 1:500,and about 500:1 by weight percent. The invention further provides amethod wherein the composite includes a plurality of layers. Theinvention further provides a method wherein the ratio ofpharmaceutically active substances to polymer is varied in some of thelayers. The invention further provides a method wherein each of theactive agents may have different release profiles. The invention furtherprovides a method wherein the release profile of the active agents maybe selected between rapid and delayed. The invention further provides amethod wherein a rapid profile coating releases an active agentsubstantially within one to a few hours. The invention further providesa method wherein a delayed profile coating releases an active agentand/or agents over a period of at least one month, at least two months,at least six months, or at least one year.

The invention provides an implantable medical device, comprising: anexpandable balloon catheter having an outer surface; and an adherentlayer on the balloon catheter comprising a composite of polymer and afirst active agent selected from the group consisting of resveratrol,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, and an optional second active agent selected fromthe group consisting of quercetin, pharmaceutically acceptable salts,and pharmaceutically acceptable derivatives thereof, dispersed withinthe polymer. The invention further provides an implantable medicaldevice wherein the polymer is biodegradable. The invention furtherprovides an implantable medical device wherein the polymer is abioabsorbable polymer. The invention further provides an implantablemedical device wherein the polymer is selected from the group consistingof polystyrene-polyisobutylene block copolymers, polyethyleneterephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof. The invention further provides animplantable medical device wherein the concentration of the first activeagent based on the surface area of the balloon catheter ranges fromabout 1 to about 5 m/mm², and the concentration of the optional secondactive agent based on the surface area of the balloon ranges from about1 to about 5 μg/mm². The invention further provides an implantablemedical device wherein the ratio which is in the range selected from thegroup consisting of about 1:5, about 1:2, and about 1:1 resveratrol toquercetin by weight percent. The invention further provides animplantable medical device wherein the first and second active agentsare in a ratio which is selected from the group consisting of about 1:1,about 1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4, about 4:1,about 1:5, about 5:1, about 1:10, about 10:1, about 1:20, about 20:1,about 1:25, about 25:1, about 1:50, about 50:1, about 1:100, about100:1, about 1:200, about 200:1, about 1:250, about 250:1, about 1:500,and about 500:1 by weight percent. The invention further provides animplantable medical device wherein the ratio of the first and secondactive agents to polymer is in a range selected from the groupconsisting of about 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1,about 1:4, about 4:1, about 1:5, about 5:1, about 1:10, about 10:1,about 1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,about 1:100, about 100:1, about 1:200, about 200:1, about 1:250, about250:1, about 1:500, and about 500:1 by weight percent. The inventionfurther provides an implantable medical device wherein the compositeincludes a plurality of layers. The invention further provides animplantable medical device wherein the ratio of pharmaceutically activesubstance to polymer is varied in some of the layers. The inventionfurther provides an implantable medical device wherein each of theactive agents may have different release profiles. The invention furtherprovides an implantable medical device wherein the release profile ofthe active agents may be selected between rapid and delayed. Theinvention further provides an implantable medical device wherein a rapidprofile coating releases an active agent substantially within one to afew hours. The invention further provides an implantable medical devicewherein a delayed profile coating releases an active agent and/or agentsover a period of at least one month, at least two months, at least sixmonths, or at least one year.

The invention provides the use of a catheter having an expandableballoon catheter coated with a selected polymer and a first active agentselected from the group consisting of resveratrol, pharmaceuticallyacceptable salts, and pharmaceutically acceptable derivatives thereof,and an optional second active agent selected from the group consistingof quercetin, pharmaceutically acceptable salts, and pharmaceuticallyacceptable derivatives thereof, dispersed within the polymer in themanufacture of a medicament for the treatment or preventionatherosclerosis, stenosis, restenosis, smooth muscle cell proliferation,platelet cell activation and other clotting mechanisms, occlusivedisease, or other abnormal lumenal cellular proliferation condition in alocation within the body of a patient.

The invention provides a catheter having an expandable balloon cathetercoated with a selected polymer and a first active agent selected fromthe group consisting of resveratrol, pharmaceutically acceptable salts,and pharmaceutically acceptable derivatives thereof, and an optionalsecond active agent selected from the group consisting of quercetin,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, dispersed within the polymer for use in treatmentor prevention atherosclerosis, stenosis, restenosis, smooth muscle cellproliferation, platelet cell activation and other clotting mechanisms,occlusive disease, or other abnormal lumenal cellular proliferationcondition in a location within the body of a patient.

The invention provides a method of for treating or preventingatherosclerosis, stenosis, restenosis, smooth muscle cell proliferation,platelet cell activation and other clotting mechanisms, occlusivedisease, or other abnormal lumenal cellular proliferation condition in alocation within the body of a patient in a luminal passage in a subjectcomprising: selecting a catheter having an expandable balloon catheter;coating the balloon catheter with a selected polymer and a first activeagent selected from the group consisting of resveratrol,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, and an optional second active agent selected fromthe group consisting of quercetin, pharmaceutically acceptable salts,and pharmaceutically acceptable derivatives thereof, dispersed withinthe polymer; routing the catheter through a predetermined length of theluminal passage; and expanding the balloon at one or more selectedpositions along the predetermined length. The invention further providesa method wherein the polymer is selected from the group consisting ofpolystyrene-polyisobutylene block copolymers, polyethyleneterephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof. The invention further provides amethod wherein the concentration of the first active agent based on thesurface area of the balloon catheter ranges from about 1 to about 5μg/mm2, and the concentration of the optional second active agent basedon the surface area of the balloon ranges from about 1 to about 5μg/mm2. The invention further provides a method wherein the ratio offirst and second active agents is in a range selected from the groupconsisting of about 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1,about 1:4, about 4:1, about 1:5, about 5:1, about 1:10, about 10:1,about 1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,about 1:100, about 100:1, about 1:200, about 200:1, about 1:250, about250:1, about 1:500, and about 500:1 by weight percent. The inventionfurther provides a method wherein the ratio of the first and secondactive agents to polymer is in a range of about 1:1, about 1:2, about2:1, about 1:2.5, about 2.5:1, about 1:4, about 4:1, about 1:5, about5:1, about 1:10, about 10:1, about 1:20, about 20:1, about 1:25, about25:1, about 1:50, about 50:1, about 1:100, about 100:1, about 1:200,about 200:1, about 1:250, about 250:1, about 1:500, and about 500:1 byweight percent. The invention further provides a method wherein theratio first and second active agents is in the range selected from thegroup consisting of about 1:5, about 1:2, and about 1:1 resveratrol toquercetin by weight percent. The invention further provides a methodwherein the composite includes a plurality of layers. The inventionfurther provides a method wherein the ratio of pharmaceutically activesubstances to polymer is varied in some of the layers. The inventionfurther provides a method wherein each of the active agents may havedifferent release profiles. The invention further provides a methodwherein the release profile of the active agents may be selected betweenrapid and delayed. The invention further provides a method wherein arapid profile coating releases an active agent substantially within oneto a few hours. The invention further provides a method wherein adelayed profile coating releases an active agent and/or agents over aperiod of at least one month, at least two months, at least six months,or at least one year.

The invention provides a method of electrospraying nanoparticles on to asurface of an implantable medical device selected from the groupconsisting of a catheter having an expandable balloon and anintravascular stent, the method comprising: providing a combination insolvent of a polymer and a first active agent selected from the groupconsisting of resveratrol, pharmaceutically acceptable salts, andpharmaceutically acceptable derivatives thereof, and an optional secondactive agent selected from the group consisting of quercetin,pharmaceutically acceptable salts, and pharmaceutically acceptablederivatives thereof, dispersed within the polymer combination in solventto an inner capillary of a coaxial capillary spray nozzle; providing asolvent to an outer capillary of the coaxial capillary spray nozzle;providing a difference in electrical potential between an exit tip of acoaxial capillary spray nozzle and the surface to cause electrosprayfrom the nozzles such that nanoparticles are formed and adhered to thesurface to provide a desired drug release profile. The invention furtherprovides a method wherein the polymer is selected from the groupconsisting of polystyrene-polyisobutylene block copolymers, polyethyleneterephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof.

The invention further provides a method wherein each of the two activeagents may have different release profiles. The invention furtherprovides a method wherein the release profile of the active agent may beselected between rapid and delayed. The invention further provides amethod wherein a rapid profile coating releases an active agentsubstantially within one to a few hours. The invention further providesa method wherein a delayed profile coating releases an active agentand/or agents over a period of at least one month, at least two months,at least six months, or at least one year.

invention provides a method of coating an implantable medical deviceselected from the group consisting of a catheter having an expandableballoon and an intravascular stent, the method comprising: providing acoating solution comprising a polymer and a first active agent selectedfrom the group consisting of resveratrol, pharmaceutically acceptablesalts, and pharmaceutically acceptable derivatives thereof, and anoptional second active agent selected from the group consisting ofquercetin, pharmaceutically acceptable salts, and pharmaceuticallyacceptable derivatives thereof; providing an implantable medical device;submerging the entire implantable medical device, or an entire sectionof the implantable medical device, in the coating solution; withdrawingthe implantable medical device from the coating solution; and drying theimplantable medical device. The invention further provides a methodwherein the polymer is selected from the group consisting ofpolystyrene-polyisobutylene block copolymers, polyethyleneterephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, Parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof. The invention further provides amethod wherein each of the active agents may have different releaseprofiles. The invention further provides a method wherein the releaseprofile of the active agents may be selected between rapid and delayed.The invention further provides a method wherein a rapid profile coatingreleases an active agent substantially within one to a few hours. Theinvention further provides a method wherein a delayed profile coatingreleases an active agent and/or agents over a period of at least onemonth, at least two months, at least six months, or at least one year.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a diagram of a stent design according to an embodiment of thepresent invention.

FIG. 2 is a bar chart showing the effects of resveratrol onproliferation of rat aortic vascular smooth muscle cells according tothe present invention.

FIG. 3 is a bar chart showing the effect of resveratrol on NFκBactivation in vascular smooth muscle cells

FIG. 4 is a set of three digital photographs showing carotid arteriesfrom wildtype controls, wildtype mice subjected to endothelialdenudation, and wildtype mice administered resveratrol for 4 weeks andsubjected to endothelial denudation according to the present invention.

FIG. 5 is a bar chart showing the effects of oral resveratroladministration on NFκB activation in mouse aorta after carotid arteryendothelial denudation according to the present invention.

FIG. 6 is a set of bar charts showing the effects of oral resveratroladministration on vascular nitric oxide production, as assessed bymeasurement of its stable metabolite, nitrite, in aortas of eitherwildtype mice or ER-deficient mice according to the present invention.

FIG. 7 is a bar chart showing the effect of resveratrol on neointimalarea in mice.

FIG. 8 is a schematic showing the mechanism for resveratrol-mediatedinhibition of VSMC proliferation according to the present invention.

FIG. 9 is a bar chart showing the effects of oral administration with 50mg/kg resveratrol (RESV), 10 mg/kg quercetin (QUER), or resveratrol plusquercetin on neointimal areas in mice subjected to the carotid arteryinjury procedure. Values represent means+SEM. ANOVA revealed asignificant effect of treatment. *Denotes significance compared tocontrols. Neointimal area was determined by subtracting the luminal areafrom the area encircled by the internal elastic lamina.

FIG. 10 is a bar chart showing the release of tritiated serotonin fromplatelets incubated for 3 h with resveratrol or quercetin and thenactivated with 5 μM ADP. Values represent means+/− standard error. ANOVArevealed a significant effect of treatment. *Denotes significancecompared to vehicle.

FIG. 11 is a bar chart showing the effects of 4 weeks oraladministration of 50 mg/kg resveratrol, 10 mg/kg quercetin orresveratrol+quercetin on serum thromboxane B2 levels in B6.129 micesubjected to the carotid artery injury procedure. One-way ANOVA revealeda significant effect of treatment. *Denotes a significant changecompared to control mice.

FIG. 12 shows the effects of resveratrol and quercetin on LPS-inducedactivation of macrophages, as indicated by increases in iNOS protein(FIG. 12A) and reactive oxygen species (FIG. 12B). ANOVA revealed asignificant effect of treatment. *Indicates differences compared to LPSalone.

FIG. 13 is an isobologram for predicting the synergistic effects of aresveratrol/quercetin combination on macrophage activation. Macrophageswere incubated with differing dose ratios of resveratrol:quercetin andwere stimulated with LPS. Activation was assessed as increases in nitricoxide release. The IC₅₀'s for each dose ratio were calculated usingCaluSyn software and were used to plot the isobologram. The linedepicted above indicates the point at which additive responses areobserved (C_(I)=1). Points lying above the line indicate antagonism,whereas points below the line represent synergism.

FIG. 14 is a scanning electron microscopy images at 1,000× (left; FIGS.14A, 14C, 14E) and 20,000× magnification (right; FIGS. 14B, 14D, 14F).Images FIG. 14A and FIG. 14B are quercetin containing arbIBSnanoparticles coated using a closed morphology, while images FIG. 14Cand FIG. 14D are coated using an open morphology. FIG. 14E and FIG. 14Fare resveratrol containing arbIBS nanoparticles coated using a closedmorphology. All polymer applications were by ElectroNanospray™ process.

FIG. 15 is a bar chart showing the Lactate Dehydrogenase (LDH)cytotoxicity assay from the 48-hour endpoint experiment expressed asamount released in medium over total LDH.

FIG. 16 is a set of bar charts showing the effects of arbIBS-coatedflats on platelet activation. Bare metal flats coated using a closed oran open morphology of arbIBS polymer were incubated in Tyrode's bufferfor 48 h at 37° C. Platelets were isolated and incubated for 1 h withthe resulting conditioned Tyrode's buffer. Basal levels of activation(FIG. 16A), compared to ADP-stimulated platelet activation (FIG. 16B),were assessed by enzyme-linked immunosorbent assay for release ofplatelet-derived growth factor (PDGF) into the medium. Data areexpressed as means+/− standard error. No significant effects of thepolymer-coated flats were detected for levels of either basal orADP-stimulated activation.

FIG. 17 is a set of bar charts showing the efficacy of drug-elutingflats on inhibition of VSMC proliferation. Bare metal flats coated withresveratrol—(FIG. 17A) or quercetin—(FIG. 17B) containing arbIBS ofeither a closed or an open morphology were incubated in semi-permeabletranswell inserts in plates containing VSMC. The bromodeoxyuridine(BrdU) incorporation assay for cell proliferation was conducted after 48h of drug elution. The data are expressed as percent of control (wellsnot containing flats). *Denotes significance compared to controls.

FIG. 18 shows the release of resveratrol from smooth (closed) versusparticulate (open) matrix arbIBS polymer-coated bare metal flats.Polymer coated flats were incubated in medium at 37° C. for 28 d.Resveratrol concentration in the medium was assessed at 2 d intervalsusing high performance liquid chromatography. The data are expressed asmeans+/− standard error for cumulative release in micromolarconcentrations (FIG. 18A) compared to a percent of total drug loaded(FIG. 18B).

DETAILED DESCRIPTION OF THE INVENTION Coated Stent Reducing SMCProliferation and Platelet Activity

The following description should be viewed in the eyes of someone who isfamiliar with the state-of-the-art in this field; specific technologyshould not be considered limiting but should be taken as use ofstate-of-the-art at a moment in time. The present invention is capableof embodiments in many different forms. Preferred embodiments of theinvention are disclosed with the understanding that the presentdisclosure is to be considered as exemplifications of the principles ofthe invention and are not intended to limit the broad aspects of theinvention to the embodiments illustrated. In the following description,like reference characters designate like or corresponding partsthroughout the several views. Also in the following description, it isto be understood that such terms as “forward,” “rearward,” “front,”“back,” “right,” “left,” “upwardly,” “downwardly,” and the like arewords of convenience and are not to be construed as limiting terms.

The present invention relates generally to the maintenance of blow floodthrough stenotic areas using drug eluting stents and/or other medicaldevices; and, to increased length of time of blood flow withoutrestenosis in these areas.

Also, the present invention relates to drug-releasing stents formaintenance of blow flood through stenotic areas and to increased lengthof time of blood flow without restenosis. Preferably the stents and/orother medical devices of the present invention is/are coated with agentsthat can include but are not limited to phytochemicals such aspolyphenols. One exemplary embodiment is a DES coated with a singleagent, especially where that agent is resveratrol, which results inmaintenance of blood flow and decreased restenosis. Additionalembodiments would have multiple agents, preferably resveratrol andquercetin, coating the stent to maintain blood flow and decreaserestenosis.

According to one embodiment of the present invention, theresveratrol/quercetin combination will have equal or better efficacywith fewer side effects compared to rapamycin- or paclitaxel-coatedstents. The resveratrol/quercetin combination will likely block morepathways involved in restenosis. For example, the combination shouldinhibit VSMC proliferation, platelet activation, and inflammatoryresponses, and may even promote endothelial function. None of thecurrently-used DES promotes endothelial function orre-endothelialization.

Resveratrol

The invention, as noted above, involves the administration ofresveratrol to an individual in order to prevent restenosis and/or theprogression or recurrence of coronary heart disease.

Resveratrol may be administered in natural form, i.e., as isolated fromgrape skins, wine or other plant-derived compositions, or it may beadministered as chemically synthesized in the laboratory (e.g., usingthe methods of Moreno-Manas et al., Jeandet et al., or Goldberg et al.(1994), cited earlier herein), or as obtained commercially, e.g., fromthe Sigma Chemical Company (St. Louis, Mo.).

The resveratrol active agent may be administered in the form of apharmacologically acceptable salt, ester, amide, prodrug or analog, oras a combination thereof. However, conversion of an inactive ester,amide, prodrug or analog to an active form must occur prior to or uponreaching the target tissue or cell. Salts, esters, amides, prodrugs andanalogs of the active agents may be prepared using standard proceduresknown to those skilled in the art of synthetic organic chemistry anddescribed, for example, by J. March, “Advanced Organic Chemistry:Reactions, Mechanisms and Structure,” 4th Ed. (New York:Wiley-Interscience, 1992). For example, basic addition salts areprepared from the neutral drug using conventional means, involvingreaction of one or more of the active agent's free hydroxyl groups witha suitable base. Generally, the neutral form of the drug is dissolved ina polar organic solvent such as methanol or ethanol and the base isadded thereto. The resulting salt either precipitates or may be broughtout of solution by addition of a less polar solvent. Suitable bases forforming basic addition salts include, but are not limited to, inorganicbases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,calcium hydroxide, trimethylamine, or the like. Preparation of estersinvolves functionalization of hydroxyl groups which may be presentwithin the molecular structure of the drug. The esters are typicallyacyl-substituted derivatives of free alcohol groups, i.e., moietieswhich are derived from carboxylic acids of the formula RCOOH where R isalkyl, and preferably is lower alkyl. Esters can be reconverted to thefree acids, if desired, by using conventional hydrogenolysis orhydrolysis procedures. Preparation of amides and prodrugs can be carriedout in an analogous manner. Other derivatives and analogs of the activeagents may be prepared using standard techniques known to those skilledin the art of synthetic organic chemistry, or may be deduced byreference to the pertinent literature (see U.S. Pat. No. 6,022,901).

Non-limiting examples of derivatives of cis- and trans-resveratrol arethose in which the hydrogen of one or more of the compounds' hydroxylgroups is replaced to form esters or ethers (for example, see FormulaI). Ether formation examples include, but are not limited to, theaddition of alkyl chains such as methyl and ethyl groups, as well asconjugated mono- or disaccharides such as glucose, galactose, maltose,lactose and sucrose. Additional modifications at the hydroxyl groupsmight include glucuronidation or sulfation.

Esterification products include, but are not limited to, compoundsformed through the addition of amino acid segments such as RGD or KGD orother compounds resulting from the reaction of the resveratrol hydroxylgroups with other carboxylic acids.

Additional derivatives include, but are not limited to, those compoundsthat result from the oxidative dimerization of or functional groupaddition to the parent resveratrol compound or to a functionalizedresveratrol variant. Examples of these compounds include materialsresulting from the addition of hydroxyl, methoxy and ethoxy groups atthe 4, 2′, and 3′ positions. Dimerization results from the reaction ofthe ethane bond of one resveratrol molecule with one of the hydroxylgroups on a second resveratrol molecule resulting in the formation of afused ring system. Alkylation at the 4, 2′, and 3′ positions createsother derivatives through the addition of groups including, but notlimited to, methyl, ethyl, and propyl, as well as the addition of largercarbon chains such as 4-methyl-2-pentene, 4-methyl-3-pentene andisopentadiene.

Additional derivatives include, but are not limited to, compounds thatarise from the loss of any of the hydroxyl groups of the parentmolecule, addition of hydroxyl groups at alternate positions, and anycompound that may arise from the previously mentioned reactions toprovide a functionalized variant of the dehydroxylated compound.

Examples of Resveratrol Derivatives

Additional Uses for Resveratrol

Resveratrol may be involved in many pathways of restenosis. Thus,according to the present invention, resveratrol may address many if notall targets causing a problem from restenosis. For instance, it providesanti-inflammatory benefits and promotes endothelial cell function.Reports have shown that resveratrol stimulates the growth of endothelialprogenitor cells, both in vivo and in vitro (see J. Gu, et al., 2006,Effects of resveratrol on endothelial progenitor cells and theircontributions to reendothelialization in intima-injured rats. JCardiovasc Pharmacol., 47(5): 711-721). This may be a key step inre-endothelialization.

Resveratrol also increases endothelial nitric oxide synthase activity(see Wallerath T et al., “Resveratrol, a polyphenolic phytoalexinpresent in red wine, enhances expression and activity of endothelialnitric oxide synthase.” Circulation. 2002 Sep. 24; 106(13):1652-8.)Further, resveratrol enhances endothelium-dependent vasorelaxation (RushJ W, Quadrilatero J, Levy A S, Ford R J. Chronic resveratrol enhancesendothelium-dependent relaxation but does not alter eNOS levels in aortaof spontaneously hypertensive rats. Exp Biol Med (Maywood). 2007 June;232(6):814-22). Therefore, utilizing resveratrol in a DES and/or othermedical device according to the present invention provides amulti-faceted approach to reducing restenosis and improving blood flowafter stent implantation.

Quercetin

Another exemplary compound for use in the compositions of the presentinvention is quercetin or an analog of quercetin. Quercetin is typicallyfound in plants as glycone or carbohydrate conjugates. Quercetin itselfis an aglycone or aglucon. That is, quercetin does not possess acarbohydrate moiety in its structure. Analogs of quercetin include itsglycone conjugates include rutin and thujin. Rutin is also known asquercetin-3-rutinoside. Thujin is also known as quercitrin,quercetin-3-L-rhamnoside, and 3-rhamnosylquercetin. Onions containconjugates of quercetin and the carbohydrate isorhamnetin, includingquercetin-3,4′-di-O-beta glucoside, isorhamnetin-4′-O-beta-glucoside andquercetin-4′-O-beta-glucoside. Quercetin itself is practically insolublein water. The quercetin carbohydrate conjugates have much greater watersolubility then quercetin.

Quercetin is known chemically as2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one and3,3′,4′5,7-pentahydroxy flavone.

Quercetin is a phenolic antioxidant and has been shown to inhibit lipidperoxidation. In vitro and animal studies have shown that quercetininhibits degranulation of mast cells, basophils and neutrophils. Suchactivities account, in part, for quercetin's anti-inflammatory andimmunomodulating activities. Other in vitro and animal studies show thatquercetin inhibits tyrosine kinase and reduces the activation of theinflammatory mediator, NF-κB. Further activities of quercetin includeanti-viral and anti-cancer activity. Quercetin is further known toinhibit aldose reductase. A quercetin or an analog thereof for use inthe present invention can be an inhibitor of tyrosine kinases. The mostimportant biologic activities of quercetin are its inhibition ofplatelet activation plus its anti-inflammatory properties, as theinteraction of these two effects can reduce the incidence ofthrombogenesis associated with current generation DES. Quercetininhibits both platelet activation and platelet aggregation. It enhancesplatelet-derived nitric oxide to inhibit the activation of a proteinkinase C-dependent NADPH oxidase. In addition, quercetin inhibitsplatelet aggregation through its inhibition of phosphoinositide kinase.Further properties of quercetin or its analogs that are relevant in thecontext of the present invention include: inhibition of cell cycle,inhibition of smooth muscle cell proliferation and/or migration.Suitable analogs/derivatives of quercetin include its glycone conjugatesrutin and thujin (See U.S. Patent Application Publication No.2007/0212386 (Patravale et al.)).

Quercetin and/or its analogs may be capable of exerting the aboveactivities when used singly. However, the above properties of quercetinand/or its analogs may be further enhanced by exploiting the synergybetween quercetin and/or its analogs and further therapeutic agents (asdisclosed herein), such as resveratrol and/or its derivatives.

In one embodiment, the combination of polymer and pharmaceuticallyactive agent comprise a combination of pharmaceutically active agents.If more than one pharmaceutically active agent is used, they can bepresent in combination in the same layer, or in separate polymer layers.Exemplary combinations include resveratrol plus quercetin separately orin combination in one or more coatings and resveratrol or quercetinalone or in combination in one or more coatings.

Exemplary derivatives of quercetin are those in which the hydrogen ofone or more of the compounds' hydroxyl groups, most commonly the 3hydroxyl is replaced to form esters or ethers (see for example FormulaVII). Ether formation examples include, but are not limited to, theaddition of alkyl chains such as methyl and ethyl groups, as well asdeoxy sugars such as fucose and rhamnose. Esterification productsinclude, but are not limited to; compounds formed through the reactionof carboxylic acid containing materials such as acetic acid, propionicacid and palmitic acid. Urethane derivatives of quercetin include, butare not limited to; amino acid ester carbamates formed by the additionof materials such as benzyl 2-isocyanatoacetate and (S)-methyl2-isocyanatopropanoate.

Additional quercetin derivatives include, but are not limited to,compounds that can be described as metabolites formed by the addition ofsugar-like derivatives such as glucuronyl groups at any of the hydroxylpositions. Examples of these metabolites include7-O-glucuronyl-quercetin and 3′-O-glucuronyl-quercetin.

Additional derivatives include, but are not limited to, compounds thatarise from the loss of any of the hydroxyl groups of the parentmolecule, addition of hydroxyl groups at alternate positions, and anycompound that may arise from the previously mentioned reactions toprovide a functionalized variant of the dehydroxylated compound.

Examples of Quercetin Derivatives

Resveratrol and Quercetin

In an exemplary embodiment, resveratrol plus a small concentration ofquercetin are incorporated onto a DES and/or other medical device tomaintain blow flood through stenotic areas using stents; and, toincreased length of time of blood flow without restenosis in theseareas.

For more information on the use of resveratrol in the treatment ofrestenosis through methods other than drug-eluting stents, see U.S. Pat.No. 6,022,901, to David William Goodman, titled “Administration ofresveratrol to prevent or treat restenosis following coronaryintervention”, which is herein incorporated by reference in itsentirety.

Resveratrol is a polyphenol that has been linked to the reportedcardioprotection of red wine consumption. The reported cardioprotectiveeffects of red wine consumption was prompted by epidemiological studiesdocumenting the “French Paradox,” a term coined to describe the reducedincidence of death due to CHD in areas of southwest France. Inhabitantsof this area exhibit increased serum cholesterol and blood pressure andeat more lard and butter than do Americans, yet suffer 40% fewer deathsdue to CHD than other western societies. This paradoxical effect isattributed to their daily consumption of red wine. While epidemiologicalstudies suggest a decreased risk of CHD in populations regularlyconsuming alcohol, considerable data indicate that wine provides greaterprotection as compared to other alcoholic beverages.

Resveratrol is a phytoalexin polyphenol found in foods such as grapes,mulberries, peanuts, and grapevine. Within the grape itself, resveratrolis most abundant in the skin (ca. 50-100 μg/gm. One fluid ounce of redwine provides ˜160 μg resveratrol. The rapid conjugation of resveratrolto form glucuronides and sulfates has been argued as evidence thatorally administered resveratrol concentrations cannot approachtherapeutically useful levels. However, immediately after consumption,resveratrol can be measured in the plasma, heart, liver, and kidney.Chronic consumption further increases levels of resveratrol in tissuessuch as the heart and liver.

Quercetin is also a polyphenol present in red wine and it is likewisereported to exert protection against atherosclerosis. From apharmacological point of view, an exemplary drug combination of thepresent invention, resveratrol and quercetin, appears reasonable, redwine is actually a combination of low levels of many bioactivepolyphenols that act synergistically to exert the effects observedclinically for chronic red wine consumption.

Prior reports by other laboratories have indicated that resveratrol actsthrough a variety of mechanisms to promote vascular health. As anantioxidant polyphenol, it limits the oxidation of low-densitylipoprotein, thus inhibiting fatty streak formation. It furthermoreexhibits anti-inflammatory effects through an inhibition of NFκBactivation. Several labs have demonstrated that resveratrol promotesendothelial function by increasing eNOS activity, and a recent reportsuggests that the mechanism for this effect is an increase in eNOSphosphorylation. Resveratrol also promotes endothelial protectionagainst oxidant injury, likely via an inhibition of the activation ofNADPH oxidase. Finally, resveratrol inhibits adhesion of inflammatorycells to the vascular endothelium by inhibiting the expression ofadhesion molecules.

Prior reports demonstrate resveratrol's efficacy in inhibitingproliferation of vascular smooth muscle cells (VSMC). For example, inVSMC stimulated with the mitogens endothelin-1 and platelet-derivedgrowth factor, resveratrol inhibited cell cycle traverse, and incoronary artery smooth muscle, resveratrol inhibitedendothelin-1-induced map kinase stimulation.

The mechanisms for these effects are due in part to aresveratrol-mediated ER activation that culminates in an upregulation oftetrahydrobiopterin (BH₄) biosynthesis. The ivnetiors have demonstratedthat the resulting increase in levels of BH₄, a known NOS cofactor,promoted an elevation in NO concentration that culminated in cell cyclearrest. Effects on NO concentration are dependent upon an increase ininducible nitric oxide synthase (iNOS) activity, but not its expression.In addition to this novel ER-depedent pathway, the current inventionalso shows that resveratrol inhibits NFκB activation very potently.

Thus, according to the present invention, resveratrol exerts pleiotropiceffects on VSMC proliferation, enhancing NO production through anER-dependent pathway, but also inhibits NFκB activation through anER-independent pathway. It is the cooperativity between these twopathways that accounts for the observed effects on VSMC proliferation.

Quercetin is an inhibitor of both platelet and NFκB activation. Theaddition of quercetin to the DES of the present invention shouldpotentiate the effects of resveratrol on VSMC proliferation by boostingthe inhibitory effects on NFκB activation. Further, strong inhibitionNFκB should also potentiate resveratrol-mediated inhibition of theinflammatory component of restenosis. Addition of quercetin should alsolimit platelet activation, which is a part of the inflammatory responseto balloon angioplasty and stent implantation that leads to restenosis.Alternatively, another agent or agents which inhibit platelet activationand/or aggregation could be utilized in place of quercetin withresveratrol. Such alternative options include, but are not limited to,aspirin, ticlopidine, clopidogrel, dipyridamole, and the like.

Resveratrol has same binding site as estradiol and behaves as anER-alpha agonist, however, it has a lower binding affinity thanestradiol. This provides protection against estrogenic side effects,such as alternation of the female menstrual cycle and feminizationside-effects in males.

Alternative Drug Delivery Mechanisms

Oral dosing of resveratrol is described in U.S. Pat. Nos. 6,022,901 and6,211,247 to David William Goodman titled “Administration of resveratrolto prevent or treat restenosis following coronary intervention”, whichare herein incorporated by reference in their entirety. However,positive effects from oral dosing studies in animal models would requirehumans to ingest ˜3 g/day in a 60 kg human. Therefore, a drug releasingstent and/or other medical device should work better than oral dosagebecause of its localized targets. Regardless, the present inventioncontemplates oral delivery of a therapeutic amount of both resveratroland quercetin to prevent or treat restenosis.

Devices

In one embodiment, the device treats narrowing or obstruction of a bodypassageway in a subject in need thereof. In another embodiment, themethod comprises inserting the device into the passageway, the devicecomprising a generally tubular structure, the surface of the structurebeing coated with a composition disclosed herein, such that thepassageway is expanded. In the method, the body passageway may beselected from arteries, veins, lacrimal ducts, trachea, bronchi,bronchiole, nasal passages, sinuses, eustachian tubes, the externalauditory canal, oral cavities, the esophagus, the stomach, the duodenum,the small intestine, the large intestine, biliary tracts, the ureter,the bladder, the urethra, the fallopian tubes, uterus, vagina, thevasdeferens, and the ventricular system.

Exemplary devices include, but are not limited to, stents, ballooncomponents of balloon catheters, catheters, guidewires, sutures,staples, anastomosis devices, vertebral disks, bone pins, sutureanchors, hemostatic barriers, clamps, screws, plates, clips, vascularimplants, urological implants, tissue adhesives and sealants, tissuescaffolds, bone substitutes, intraluminal devices, and vascularsupports. For example, the device can be a cardiovascular device, suchas venous catheters, venous ports, tunneled venous catheters, chronicinfusion lines or ports, including hepatic artery infusion catheters,pacemakers and pace maker leads, and implantable defibrillators.Alternatively, the device can be a neurologic/neurosurgical device suchas ventricular peritoneal shunts, ventricular atrial shunts, nervestimulator devices, dural patches and implants to prevent epiduralfibrosis post-laminectomy, and devices for continuous subarachnoidinfusions. The device can be a gastrointestinal device, such as chronicindwelling catheters, feeding tubes, portosystemic shunts, shunts forascites, peritoneal implants for drug delivery, peritoneal dialysiscatheters, and suspensions or solid implants to prevent surgicaladhesions. In another example, the device can be a genitourinary device,such as uterine implants, including intrauterine devices (IUDs) anddevices to prevent endometrial hyperplasia, fallopian tubal implants,including reversible sterilization devices, fallopian tubal stents,artificial sphincters and periurethral implants for incontinence,ureteric stents, chronic indwelling catheters, bladder augmentations, orwraps or splints for vasovasostomy, central venous catheters.

Other exemplary devices include, but are not limited to, prostheticheart valves, vascular grafts opthalmologic implants (e.g., multinoimplants and other implants for neovascular glaucoma, drug elutingcontact lenses for pterygiums, splints for failed dacrocystalrhinostomy,drug eluting contact lenses for corneal neovascularity, implants fordiabetic retinopathy, drug eluting contact lenses for corneal injury orhigh risk corneal transplants), otolaryngology devices (e.g., ossicularimplants, Eustachian tube splints or stents for glue ear or chronicotitis as an alternative to transtempanic drains), plastic surgeryimplants (e.g., breast implants or chin implants), and catheter cuffsand orthopedic implants (e.g., cemented orthopedic prostheses).

Another exemplary device according to the invention is a stent, such asa stent comprising a generally tubular structure. A stent is commonlyused as a tubular structure disposed inside the lumen of a duct torelieve an obstruction. Commonly, stents are inserted into the lumen ina non-expanded form and are then expanded autonomously, or with the aidof a second device in situ. A typical method of expansion occurs throughthe use of a catheter-mounted angioplasty balloon which is inflatedwithin the stenosed vessel or body passageway in order to shear anddisrupt the obstructions associated with the wall components of thevessel and to obtain an enlarged lumen.

An exemplary stent is a stent for treating narrowing or obstruction of abody passageway in a human or animal in need thereof. “Body passageway”as used herein refers to any of number of passageways, tubes, pipes,tracts, canals, sinuses or conduits which have an inner lumen and allowthe flow of materials within the body. Representative examples of bodypassageways include arteries and veins, lacrimal ducts, the trachea,bronchi, bronchiole, nasal passages (including the sinuses) and otherairways, eustachian tubes, the external auditory canal, oral cavities,the esophagus, the stomach, the duodenum, the small intestine, the largeintestine, biliary tracts, the ureter, the bladder, the urethra, thefallopian tubes, uterus, vagina and other passageways of the femalereproductive tract, the vasdeferens and other passageways of the malereproductive tract, and the ventricular system (cerebrospinal fluid) ofthe brain and the spinal cord. Exemplary devices of the invention arefor these above-mentioned body passageways, such as stents, e.g.,vascular stents. There is a multiplicity of different vascular stentsknown in the art that may be utilized following percutaneoustransluminal coronary angioplasty.

Any number of stents may be utilized in accordance with the presentinvention and the invention is not limited to the specific stents thatare described in exemplary embodiments of the present invention. Theskilled artisan will recognize that any number of stents may be utilizedin connection with the present invention. In addition, as stated above,other medical devices may be utilized, such as e.g., orthopedicimplants.

Examples in patent literature disclosing stents which have been appliedin PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S.Pat. No. 4,886,062 issued to Wiktor, and U.S. Patent ApplicationPublication No. 20050186248 (Hossainy).

According to one embodiment of the present invention, the stent hasexpandable radial struts (FIG. 1). The number of struts and cells mayvary with the size of the stent, also. For a detailed description ofsuch a stent, please see U.S. Pat. No. 5,843,172 to John Y. Yan, titled“Porous medicated stent”, which is herein incorporated by reference inits entirety. For other examples such a stent, please see U.S. Pat. No.6,083,257 to Alistair Stewart Taylor, Peter William Stratford, YiannakisPetrou Yianni, and Matthew John Woodroffe titled “Braided Stent”, whichis herein incorporated by reference in its entirety; and, U.S. Pat. No.6,471,979, to Gishel New, Jeffrey W. Moses, Nicholas Kipshidze, Gary S.Roubin, and Martin B. Leon, titled “Apparatus and method for deliveringcompounds to a living organism”, which is herein incorporated byreference in its entirety. The stents and/or other medical devices maybe prepared by an initial dip coating with a silane ester primer,followed by sequential layering of a biocompatible polymer preparationcontaining 5-20% resveratrol, which will likewise be accomplished by adip-coating technique; the biocompatible polymer preparation can be ahydrophilic polyurethane. An additional layer of polymer can be placedover the final layer of drug coating for a more controlled drugdelivery. All of the described techniques for stent construction, withthe exception of the resveratrol/quercetin formulation, are well-knownto the art.

Drug Eluting Balloon Catheters and Other Devices

The invention also provides a drug coated balloon in for example, acatheter, particularly where the drug has anti-inflammatory, antiproliferative or anti-thrombotic capability or can prevent collageninduced platelet aggregation.

The catheter balloon is typically coated with layers one or more of thepolymers disclosed elsewhere in this specification particularly wherethe drug is sequestered within one or more of the polymer coatingmaterials. Preferred polymer coating materials include Poly L-Lactidepolymer (PLLA), poly(lactide-co-glycolide) (PLGA),poly(l-lactide-co-trimethylene carbonate),poly(d,l-lactide-co-trimethylene carbonate), polyvinyl alcohol (PVA) andpolyalkylene glycols (PAG) such as polyethylene glycol (PEG), albumin,gelatin, starch, cellulose, dextrans, polysaccharides, fibrinogen,poly(D,L lactide), poly(D,L-lactide-co-glycolide), poly(glycolide),poly(hydroxybutyrate), poly(alkylcarbonate), poly(orthoesters) and anyof the polymers disclosed herein for use in covalent binding of drugshaving a nucleophilic group (e.g. hydroxyl or amino) available forreaction with a complementary electrophilic group of the polymermaterial. The selected polymer coatings can be mixed, combined orcovalently bound to the selected bioactive drug in any desiredconcentration of selected drug. Two or more polymers can be combinedwith each other to form a polymer matrix. The balloon can containmultiple coatings or layers of such polymers, at least one of the layersor coatings containing a selected drug.

Other polymer materials may be used alone or together with any of theforegoing polymers as disclosed for example in Patent Cooperation Treatyapplication PCT/IN02/00173 03018082, the disclosure of which isincorporated herein by reference as if fully set forth herein.

The drug or drugs that is/are selected for inclusion in the coating onthe stents and/or other medical devices may or may not be covalentlybound to the coating polymer. Examples of the drug or drugs which may beincluded in the coating, include but are not limited to, resveratrol andquercetin for use in/on a coating on a balloon catheter. Any other ofthe drugs described in this specification can alternatively be useddepending on the treatment desired.

Dip coating techniques may be used for coating the surface of a balloonalthough other methods may also be employed such as spray coating.Coating is typically comprised of a single layer but may also comprisemultiple layers depending on the content and release profile of drugcontained in the coating. The surface may also be coated with micro ornanoformulations of the active agents. These may be pure active agentnanoparticles adhered to the surface or released from beneath apolymeric film or active agents encapsulated in polymeric micro- ornanospheres or other carriers such as liposomes. Polymeric capsules mayeither be rupturable to release their contents, may release the activeagents after enzymatic or hydrolytic break down or release the activeagents by diffusion release formulations.

Coated balloons are useful in revascularization, catheterization,balloon expansion and stent delivery procedures and methods describedherein. In a stent delivery procedure for example, a drug coated balloonaccording to the invention may also incidentally deliver drugs to vesselareas that are not situated at the localized situs of implant of astent. Such incidental delivery of drug from the surface of the balloonis of particular utility for small and tortuous vessel passages leadingup to the site of interest. Furthermore, healing andre-endothelialization of stent struts that do not carryantiproliferative agents can be facilitated by the use of drug coatedballoons.

On pressurized contact of the surface of the balloon with a blood vesselwall either as a result of stent delivery or otherwise, the drugcontaining polymer coating will adhere to the blood vessel wall surfaceand release the drug either over a very short period of time, e.g. lessthan about 45 seconds, or over a longer period of time as describedbelow, e.g. over less than about 8 minutes, depending on the selectionof the coating material(s), whether the drug is covalently bound, themiscibility/affinity of the drug for the coating material and theconcentration of the selected drug in the coating.

As a specific example, the surface of a stent, catheter balloon, orother medical device is coated with 0.1 to 15 μg of resveratrol and/orquercetin per square millimeter of device surface to enable immediaterelease of the drug on inflation. The coating resulted in a very slightincrease in profile but no recognizable change in flexibility. Therelease profile for compound or compounds in the coating on the surfaceof a stent, catheter balloon, and/or other medical device, is in a timeperiod of between about 20 and about 40 seconds, about 1 min to 100minutes, about 1 hour to 20 hours, about 1 day to 1 month, about 1 dayto 10 days, about 1 day to about 30 days, about 1 day to about 2 months,about 1 day to about 6 months, about 1 day to about 6 months, about 1day to about 1 year. Non limiting examples of delayed profile coatingrelease an active agent and/or agents over a period of at least onemonth, at least two months, at least six months, or at least one year,after implantation.

Polymers

The invention is directed to thin coatings for medical devices, morespecifically an implantable medical device, for example a stent and/orother medical device. In accordance to one embodiment, the invention isspecifically directed to a coating for a stent. The stent can be aself-expandable stent or a radially expandable stent. In othersembodiments, the stent can have a coil configuration or be made from awire or fiber-type body. The stent body can be made from a metallicmaterial, polymeric material, or a combination of metallic or polymericmaterial. The combination can be in a layered, disbursed, blended orconjugated form. In some embodiments, the metal or polymer can bebiodegradable such that the stent is intended to remain at theimplantation site for a temporary duration of time. Biodegradable,bioerodable, bioabsorbable, etc. are terms which are usedinterchangeably unless otherwise specifically intended. The stent mayhave, for example, a polymer body made from one or a combination ofpolymers. In some embodiments, the stent is from about 5 mm in length toabout 40 mm in length. In some embodiments, the stent is at least 40 mmin length. See U.S. Patent Application Publication No. 2007/0299511(Gale).

A thin coating may be disposed on the surface of the structural elementor strut. The coating can be deposited on the outer surface, innersurface and the side walls of the strut. In some embodiments, thecoating is exclusively on the outer surface, and not the inner surfaceor the side walls. In some embodiments, the coating can be on the outersurface and at least a portion of the sidewalls of the strut. In oneembodiment, the thickness of the coating is about 1 to 100 microns. Inan exemplary embodiment, the thickness of the coating can be at anyrange between about 5 and 20 microns. In an exemplary embodiment, thethickness of the coating can be, for example, about 5, about 10, about15, or about 20 microns.

In some embodiments, the coating is a pure drug or therapeutic substancelayer. In some embodiments, the coating is a combination of more thanone drug or therapeutic substance without any polymers. In someembodiments the coating can be a combination of at least one polymer andat least one drug or therapeutic substance. Combination is defined asblending, mixing, dispersing, conjugating, and/or bonding of thedrug/therapeutic substance to the polymer. The coating polymer can bethe same as or different than a polymer from which the stent is made. Atleast one of the polymers for the coating can be the same or differentthan at least one of the polymers of the stent structure.

In some embodiments, the coating can include a primer layer and/or atopcoat layers or sub-layers. The primer layer will be beneath thedrug/therapeutic substance layer and the topcoat layer above it. Boththe primer layer and the topcoat layer can be without anydrugs/therapeutic substances. In some embodiments, some drug mayincidentally migrate into the primer layer or region. The topcoat layerreduces the rate of release of the drug and/or provides forbiobeneficial properties.

The thin coating can be deposited by spray application, electrostaticapplication, “ink-jet”-type application, plasma deposition and the like.These processes are known in the art. A coating composition includingpolymer(s), solvent(s), and optionally drug(s)/therapeutic substance(s)can be used, for example. In some embodiments, the amount of solventincluded in the composition can be low so as to allow for formation ofthe thin coating. In some embodiments, the method of coating may includemodifying at least one process parameter of the spraying so that aweight percent of solvent in coating material applied on the polymericsurface is less than about 30 wt %, 20 wt %, 15 wt %, or more narrowly,10 wt %.

The stent or the coating can be made from a material including, but arenot limited to, poly(N-acetylglucosamine)(Chitin), Chitosan,poly(hydroxyvalerate), poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),polyorthoester, polyanrhydride, poly(glycolic acid), poly(glycQlide),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid),poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyester amide, poly(glycolic acid-co-trimethylene carbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules(such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid), polyurethanes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers other than polyacrylates, vinyl halide polymers andcopolymers (such as polyvinyl chloride), polyvinyl ethers (such aspolyvinyl methyl ether), polyvinylidene halides (such as polyvinylidenechloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose. Another type of polymer based on poly(lacticacid) that can be used includes graft copolymers, and block copolymers,such as AB block-copolymers (“diblock-copolymers”) or ABAblock-copolymers (“triblock-copolymers”), or mixtures thereof.

Additional representative examples of polymers that may be especiallywell suited for use in fabricating or coating the stent include ethylenevinyl alcohol copolymer (commonly known by the generic name EVOH or bythe trade name EVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluororpropene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

The stent can also be made from the following metallic materials oralloys: cobalt chromium alloy (ELGILOY), stainless steel (316L),“MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

The coating can be made from the following materials: poly(ester amide),polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalkanaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyurethanes, polyphosphazenes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride, polyvinylethers, such as polyvinyl methyl ether, polyvinylidene halides, such aspolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate, copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxides such aspoly(ethylene oxide), poly(propylene oxide), poly(ether ester),polyalkylene oxalates, polyphosphazenes, phosphoryl choline, choline,poly(aspirin), polymers and co-polymers of hydroxyl bearing monomerssuch as HEMA, hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, collagen, dextran, dextrin, fragments and derivativesof hyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, or combinations thereof. In some embodiments, thesubstrate coating described herein can exclude any one of theaforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

In some embodiments, the coating preferably includes a fluoropolymersuch as a Solef™ polymer (e.g., PVDF-HFP).

In some embodiments, the coating can be made from or further include abiobeneficial material. The biobeneficial material can be polymeric ornon-polymeric. The biobeneficial material is preferably substantiallynon-toxic, non-antigenic and non-immunogenic. A biobeneficial materialis one that enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent.

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol), copoly(ether-esters) (e.g.PEO/PLA), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, poly(ethylene glycol) acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen,dextran, dextrin, hyaluronic acid, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, silicones, PolyActive™, and combinations thereof.

The term PolyActive™ refers to a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks(PEGT/PBT). PolyActive™ is intended to include AB, ABA, BAB copolymershaving such segments of PEG and PBT (e.g., poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol)(PEG-PBT-PEG).

In a preferred embodiment, the biobeneficial material can be a polyethersuch as poly(ethylene glycol) (PEG) or polyalkylene oxide.

Dosages

On-device dosages of at least one pharmaceutically active agent oragents may be determined by means known in the art. Typically, thedosage is dependent upon the particular drug employed and medicalcondition being treated to achieve a therapeutic result. In oneembodiment, the amount of drug represents about 0.001 percent to aboutseventy percent of the total coating weight, or about 0.01 percent toabout sixty percent of the total coating weight. In one embodiment, theweight percent of the therapeutic agents in the carrier or polymercoating is 1% to 50%, 2% to 45, 5% to 40, or 10 to 35%. In anotherembodiment, it is possible that the drug may represent as little as0.0001 percent to the total coating weight. In another embodiment, theamount of selected drugs loaded onto a 16 mm long stent range from about30 to about 105 micrograms per coating layer.

In an exemplary embodiment, the dosage or concentration of, e.g.,resveratrol and/or quercetin based on surface area on a typical coronarystent and/or other medical device can range from about 0.1 to about 5μg/mm², or more than about 0.7 μg/mm² (at lower dosage restenosis ratesare higher), or less than about 3.0 μg/mm² (higher will be cytotoxic),or ranging from 1.0 and 1.8 μg/mm², and or about 1.4 μg/mm². In anexemplary embodiment, the dosage or concentration of, e.g., resveratroland/or quercetin based on surface area on a typical coronary stentand/or other medical device can range from about 0.5 μg/mm² to about 35μg/mm². In an exemplary embodiment, the dosage or concentration of,e.g., resveratrol and/or quercetin based on surface area on a typicalcoronary stent and/or other medical device can range from about 1 μg/mm²to about 100 μg/mm². In an exemplary embodiment, the dosage orconcentration of, e.g., resveratrol and/or quercetin based on surfacearea on a typical coronary stent and/or other medical device can rangefrom about 1 μg/mm² to about 2 μg/mm². In an exemplary embodiment, thedosage or concentration of, e.g., resveratrol and/or quercetin based onsurface area on a typical coronary stent and/or other medical device canrange from about 1 μg/mm² to about 5 μg/mm². In an exemplary embodiment,for a typical series of coronary stent varying in length from 8.00 to39.00 mm, the total resveratrol and/or quercetin content will vary from50 μg to 250 μg. Suitable dosaging for drug-eluting stents is furtherdescribed in U.S. Pat. No. 6,908,622, the disclosure of which isincorporated herein by reference.

The dosage or concentration of e.g. resveratrol and/or quercetin basedon surface area on a typical coronary stent may be is 0.1 and 5 μg/mm²In another embodiment, the dosage is more than about 0.7 μg/mm² (atlower dosage restenosis rates are higher) and less than about 3.0μg/mm², such as ranging from 1.0 and 1.8 μg/mm², e.g., about 1.4 μg/mm².Typically, the amount of resveratrol and/or quercetin will increaselinearly with the length of the stent. For example, for a typical seriesof coronary stent varying in length from 8.00 to 39.00 mm, the totalresveratrol and/or quercetin content will vary from 50 μg to 250 μg.

The dosage or concentration of a flavonoid or derivative thereof basedon surface area on a stent (e.g. a typical coronal stent) may be is 0.1and 40 μg/mm². In one embodiment, the dosage of a flavonoid orderivative thereof based on surface area of a device of the invention ismore than about 0.2, 0.5, 1.0, 2.0, 5.0 or 10 μg/mm². In anotherembodiment, the dosage of a flavonoid or derivative thereof based onsurface area of a device of the invention is less than about 30.0, 20.0,15.0, 10.0, 5.0, 3.0 or 2.0 μg/mm². Generally, the amount of theflavonoid or derivative thereof will increase linearly with the lengthof the stent. For example, for a typical series of coronary stentvarying in length from 8.00 to 39.00 mm, the total flavonoid (orderivative thereof) content will vary from 28 μg to 3500 μg.

Method of Treatment

In one embodiment, the implantable devices disclosed herein areimplanted in a subject in need thereof to achieve a therapeutic effect,e.g., therapeutic treatment and/or prophylactic/preventative measures.Those in need of treatment may include individuals already having aparticular medical disease as well as those at risk for the disease(e.g., those who are likely to ultimately acquire the disorder). Atherapeutic method can also result in the prevention or amelioration ofsymptoms, or an otherwise desired biological outcome, and may beevaluated by improved clinical signs, delayed onset of disease,reduced/elevated levels of lymphocytes and/or antibodies.

In one embodiment, the method is used for treating at least one diseaseor condition associated with vascular injury or angioplasty. Angioplastymay be performed as part of “revascularization” treatment for“artherosclerosis,” which as used herein means diseases in which plaque,made up of cholesterol, fats, calcium, and scar tissue, builds up in thewall of blood vessels, narrowing the lumen and interfering with bloodflow. “Revascularization,” as used herein means any treatment thatre-establishes brisk blood flow through a narrowed artery, includingbypass surgery, angioplasty, stenting, and other interventionalprocedures. Secondary complications following revascularization mayinclude restenosis, neointima, neointimal hyperplasia and thrombosis.“Restenosis,” as used herein is defined as the re-narrowing of an arteryin the same location of a previous treatment; clinical restenosis is themanifestation of an ischemic event, usually in the form of recurrentangina. “Neointima,” as used herein is defined as the scar tissue madeup of cells and cell secretions that often forms as a result of vesselinjury following angioplasty or stent placement as part of the naturalhealing process. “Neointimal hyperplasia,” as used herein meansexcessive growth of smooth muscle cells from the inner lining of theartery. After angioplasty and/or stenting, excessive growth of thesecells can narrow the artery again. “Thrombosis,” as used herein meansthe formation of a blood clot within a blood vessel or the heart cavityitself and a “thrombus” is a blood clot.

Three pathophysiological phases can be distinguished subsequent torevascularization. Stage I, the thrombotic phase (days 0-3 afterrevascularization). This stage consists of rapid thrombus formation. Theinitial response to arterial injury is explosive activation, adhesion,aggregation, and platelet deposition. The platelet thrombus mayfrequently be large and can grow large enough to occlude the vessel, asoccurs in myocardial infarction. Within 24 hours, fibrin-rich thrombusaccumulates around the platelet site. Two morphologic features areprominent: 1) platelet/fibrin, and 2) fibrin/red cell thrombus. Theplatelets are densely clumped at the injury site, with the fibrin/redcell thrombus attached to the platelet mass.

Stage II, the recruitment phase (days 3-8). The thrombus at arterialinjury sites develops an endothelial cell layer. Shortly after theendothelial cells appear, an intense cellular infiltration occurs. Theinfiltration is principally monocytes that become macrophages as theyleave the bloodstream and migrate into the subendothelial muralthrombus. Lymphocytes also are present, and both types of cellsdemarginate from the bloodstream. This infiltrate develops from theluminal side of the injured artery, and the cells migrate progressivelydeeper into the mural thrombus.

Stage III, the proliferative phase: (day 8 to final healing).Actin-positive cells colonize the residual thrombus from the lumen,forming a “cap” across the top of the mural thrombus in this finalstage. The cells progressively proliferate toward the injured media,resorbing thrombus until it is completely gone and replaced byneointimal cells. At this time the healing is complete. In the pig thisprocess requires 21-40 days, depending on residual thrombus thickness.Smooth muscle cell migration and proliferation into the degeneratedthrombus increases neointimal volume, appearing greater than that ofthrombus alone. The smooth muscle cells migrate from sites distant tothe injury location, and the resorbing thrombus becomes a bioabsorbable“proliferation matrix” for neointimal cells to migrate and replicate.The thrombus is colonized at progressively deeper levels untilneointimal healing is complete.

In one embodiment, the method of the invention can be used to treatthese conditions subsequent to revascularization, such as thoseconditions subsequent to any of the three stages described above, e.g.,activation, adhesion, aggregation, platelet deposition, thrombosis,platelet aggregation, proliferation, and neointima.

In one embodiment, the active agent and/or agents are for the preventionor treatment of restenosis subsequent to angioplasty, such as theinhibition of neointimal hyperplasia subsequent to angioplasty.

In one embodiment, the methods of the invention are directed to theprevention of acute, subacute and chronic secondary complicationsassociated with angioplasty. Such secondary complications subsequent toand/or associated with angioplasty are defined herein above and include,e.g., restenosis, neointima, neointimal hyperplasia, thrombosis andinflammation.

In one embodiment, the methods disclosed herein are directed to treatingundesired cell proliferation, which is often a component of many diseaseprocesses. Undesired cell growth can be a component of restenosis, therecurrence of stenosis or artery stricture after corrective surgery.Restenosis occurs after coronary artery bypass (CAB), endarterectomy,heart transplantation, or after angioplasty, atherectomy, laser ablationor stenting. Restenosis is the result of injury to the blood vessel wallduring the lumen opening procedure. In some patients, the injuryinitiates a repair response that is characterized by smooth muscle cellproliferation referred to as “hyperplasia” in the region traumatized bythe angioplasty. This proliferation of smooth muscle cells re-narrowsthe lumen that was opened by the angioplasty within a few weeks to a fewmonths, thereby necessitating a repeat angioplasty or other procedure toalleviate the restenosis.

The therapeutic compounds disclosed herein will be delivered locally toreduce side effects from high dose systemic delivery. The local deliveryoptions can include release from a drug eluting stent, delivery by adrug eluting balloon or local delivery/activation by remote techniques.The latter could include systemic delivery of nanocomposite particlesinto the circulation coupled by remote capture or release of thetherapeutic agents by acoustic, electrical, magnetic or optical energysources. (e.g., carotid or other peripheral vesselendarterectomy,vascular bypass, stent or prosthetic graft procedure). For example, acoated stent or device as disclosed herein may be implanted at thevascular site of interest for controlled release of the pharmaceuticallyactive agents over a desired time period.

Method of Making a Coated Drug Eluting Stent or Balloon Catheter

The practice of coating implantable medical devices with a synthetic orbiological active or inactive agent is known. Numerous processes havebeen proposed for the application of such a coating. Soaking or dippingthe implantable device in a bath of liquid medication is suggested byU.S. Pat. No. 5,922,393 to Jayaraman, soaking in an agitated bath, U.S.Pat. No. 6,129,658 to Delfino et al. Devices introducing heat and/orultrasonic energy in conjunction with the medicated bath are disclosedin U.S. Pat. No. 5,891,507 to Jayaraman and U.S. Pat. No. 6,245,104 toAlt. The device of U.S. Pat. No. 6,214,115 to Taylor et al. suggestsspraying the medication by way of pressurized nozzles, see U.S. PatentApplication No. 2006/0156976 (Shekalim).

Initially such coatings were applied at the time of manufacture.Wrapping the implantable device with medicated conformal film isdisclosed in U.S. Pat. No. 6,309,380 BI to Larson et al. Dipping orsoaking in a medicated bath just prior to implantation are suggested inU.S. Pat. No. 5,871,436 to Eury, U.S. Pat. No. 6,730,120 to Berg et al.,and U.S. Pat. No. 6,1171,232 to Papandreou et al. U.S. Pat. No.6,395,326 BI to Wu provides a bathing chamber for use with specificimplantable device such as the stent deployed on the balloon of acatheter.

Each of the methods and devices intended for use just prior toimplantation, listed above, deposit the coating material onto any andall surfaces that are exposed to the coating. This may result indepositing coating material on surfaces on which the coating is unwantedor undesirable. Further, the coating may crack or break away when theimplantable is removed from the implantation apparatus. An example ofthis would be a stent deployed on a catheter balloon. As the balloon isinflated and the stent is expanded into position, the coating may crackalong the interface between the stent and the balloon. These cracks maylead to a breaking away of a portion of the coating from the stentitself. Similar problems can occur in cases where the coating techniquefails to prevent inadvertent overlapping with the edges (e.g., internalsurfaces along the edges) of various devices (e.g., struts of stents).This, in turn, may affect the medicinal effectiveness of the coating,and negatively affect the entire medical procedure.

It is known to use Ink-Jet technology to apply a liquid to selectedportion of a surface. In the paper “Applications of Ink-Jet PrintingTechnology to BioMEMS and Microfluidic Systems,” presented at the SPICConference on Microfluidics and BioMEMS, October, 1, the authors,Patrick Cooley, David Wallace, and Bogdan Antohe provide a fairlydetailed description of Ink-Jet technology and the range of itsmedically related applications.

The present invention incorporates at least one compound coated onto avascular stent and/or other medical device. For a detailed descriptionof such a stent and/or other medical device and how it may be coated,please see U.S. Pat. No. 7,247,338, to David Y. H. Pui and Da-Ren Chen,titled “Coating medical devices”, which is herein incorporated byreference in its entirety. For other examples of how such a stent may becoated, please see U.S. Pat. No. 6,093,557, to David Y. H. Pui andDa-Ren Chen, titled “Electrospraying apparatus and method forintroducing material into cells,” U.S. Pat. No. 6,399,362 to David Y. H.Pui and Da-Ren Chen, titled “Electrospraying apparatus and method forintroducing material into cells,” U.S. Pat. No. 6,746,869 to David Y. H.Pui and Da-Ren Chen, titled “Electrospraying Apparatus and Method forCoating Particles,” and U.S. Pat. No. 6,764,720, to David Y. H. Pui andDa-Ren Chen, titled “High mass throughput particle generation usingmultiple nozzle spraying” which are herein incorporated by reference intheir entirety.

Preferably the method of making a coated stent according to the presentinvention incorporates a ElectroNanospray™ process for creating thecoating because of its uniformity of drug coverage, even coating, andlack of pooling and webbing. Additionally, its use of a dual capillaryco-axial nozzle allows for the delivery of multiple agents, as isincluded in this invention. However, the present invention is notlimited to this technology for coating. Another technology, which is notlimiting, that could be used is the presence of multiple polymers forsupport.

All coating processes are to be optimized according to the presentinvention for variables including the photosensitivity of resveratroland quercetin, the levels of resveratrol required for elicitingefficacious results, synergistic effects between the two drugs thatresult in differing levels of drug loading, and necessary processingsteps to decrease or eliminate the possible oxidation of said compounds.

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLES Example 1

Determining whether quercetin potentiates the vascular protectiveeffects of resveratrol in vivo, utilizing a mouse carotid artery injurymodel. Female B6.129 mice were administered a high fat diet, in somecases mixed together with 50 mg/kg resveratrol (RESV), 10 mg/kgquercetin (QUER), or resveratrol plus quercetin, for 2 weeks. Thecarotid artery injury procedure was conducted and the animals were fedthe high fat diet plus polyphenols for an additional two weeks. Theanimals were then sacrificed, and the carotid arteries were excised andassessed for neointimal areas. The results indicate that oral treatmentwith resveratrol dramatically reduced neointimal area. Though treatmentwith quercetin alone exhibited no significant effect, it potentiated theeffects of resveratrol when the two polyphenols were administered incombination.

Example 2

Effects of resveratrol/quercetin combination on platelet activation.Prior reports suggest the efficacy of quercetin, and to some extent,resveratrol, in reducing platelet activation and aggregation. Thus, theaddition of quercetin to the drug eluting stent should make thedescribed invention preferable to current generation DES and/or othermedical devices that have the undesired side effect of thrombogenesis.To determine the efficacy of these compounds in reducing plateletactivation, platelets isolated from healthy, male donors were incubatedwith resveratrol, quercetin, or resveratrol plus quercetin. The doseswere selected based on prior studies. In experiments examining effectson VSMC proliferation, resveratrol's EC₅₀ for inhibiting DNA synthesiswas 18 μM, while its EC₅₀ for reducing numbers of cells was 25 μM. Cellswere treated with the lower dose, 18 μM resveratrol, and added to this10 and 15 μM quercetin, doses about half its reported EC₅₀ for reducingVSMC proliferation. Doses of each that were slightly below their maximaleffective doses were utilized, so as to be able to discern the additiveor synergistic effects of the drugs. The polyphenol treatments exhibiteddramatic effects on platelet activation. Treatment with 18 μMresveratrol reduced serotonin release by ˜60%, and incubation with 10-15μM quercetin reduced serotonin release by 40-50% (FIG. 10). Cotreatmentwith 18 μM resveratrol plus 10 μM quercetin reduced the activation by65% compared to controls, and cotreatment with 15 μM quercetin reducedactivation by 80%. Thus, these experiments demonstrate that quercetinpotentiated the effects of resveratrol on platelet activation.

Example 3

In vivo experiments determining the efficacy of combined treatment withresveratrol/quercetin in reducing platelet activation. To confirm the invitro experiments in an in vivo rodent model, the effects of oraladministration of 50 mg/kg resveratrol were compared to treatment withresveratrol plus 10 mg/kg quercetin in the mouse carotid artery injurymodel. Plasma levels of thromboxane B₂ (TBX₂), a known marker forplatelet activation, were assessed. Though resveratrol treatment alonehad no significant effect on plasma TXB₂ levels (FIG. 11), treatmentwith quercetin alone reduced TXB₂ levels by 40%, and treatment withquercetin plus resveratrol reduced TXB₂ by 70%. Thus, treatment with aresveratrol/quercetin combination induces additive and synergisticeffects on platelet activation in vivo.

Example 4

Effects of resveratrol/quercetin combination on the activation ofinflammatory cells. Resveratrol is well-known to inhibit inflammatoryresponses via inhibition of NFkB activation. To test the efficacy of aresveratrol/quercetin combination in inhibiting the activation ofmacrophages, effects of polyphenol treatments either alone or incombination with quercetin were assessed in cultures oflipopolysaccharide (LPS) stimulated macrophages. Macrophage activationwas determined by increases in protein levels of inducible nitric oxidesynthase (iNOS) and by levels of reactive oxygen species (ROS).Treatment with 18 μM resveratrol reduced iNOS protein levels by ˜25%, inagreement with prior reports documenting the anti-inflammatory activityof resveratrol (FIG. 12). However, quercetin more potently diminishedmacrophage activation, reducing iNOS protein by ˜75 and 90% at 10 and 15μM, respectively. In addition, the combination of 18 μM resveratrol plus10-15 μM quercetin virtually abolished all macrophage activation. Thedata for ROS production were similar. This compilation of data thusdemonstrates the efficacy of the drug combination in inhibiting theactivation of inflammatory cells.

Example 5

Isobolograms for the determination of synergistic dose ratios for aresveratrol/quercetin combination. To determine the dose ratios forachieving maximal synergistic effects, activation in LPS-stimulatedcells macrophages incubated with constant dose ratios of resveratrol andquercetin was measured. The IC₅₀ for each dose ratio was calculatedusing CalcuSyn software, and these concentrations were used to constructan isobologram (FIG. 13). Dose ratios exhibiting synergism were 1:5,1:2, and 1:1 resveratrol:quercetin. These dose ratios exhibitedcombination indices (CI values) of ˜0.5. Briefly, CI=1 denotes additiveeffects, CI>1 denotes antagonism, and CI<1 indicates synergism. As anexample of the synergistic effects of the resveratrol/quercetincombination, the IC₅₀'s for individual treatments of resveratrol andquercetin were 3.5 and 2.4 μM, respectively. However, when the drugswere administered at a 1:1 dose ratio, 50% inhibition could be achievedat 0.9 μM concentrations of each compound.

Example 6

Development of drug eluting stent models for in vitro analysis ofefficacy. For the purposes of modeling DES release and biocompatibilityin an inexpensive in vitro system, stainless steel flat surfaces coatedwith drug-containing polymer were utilized. The bare metal flats(0.2″×0.3″) were coated with a polyisobutylene-polystyrene triblockcopolymers containing the active agents with two distinct surfacemorphologies—smooth and nanoparticulate (high surface area) matrices.The ElectroNanospray™ process for depositing drug-containingnanoparticles, typically 50-300 nm in diameter, was utilized so as toachieve uniformity of drug coverage, even coating, and lack of pooling.Differences in coating morphologies can culminate in differences in drugrelease characteristics. Initial biocompatibility testing on bothconformations was conducted. Each coating type was loaded with twoconcentrations of either resveratrol or quercetin.

The coating process needs to be able to minimize variation so that eachflat, and eventually each stent, releases the target amount of drug at adesired rate. FIG. 14 illustrates scanning electron microscopy (SEM)images of drug-containing polymer applied using the ElectroNanospray™process. FIG. 14 furthermore compares polyisobutylene-polystyrenetriblock copolymer surfaces of both open and closed morphologiescontaining resveratrol and quercetin nanoparticles. These images displaya uniform coating with either smooth (closed) or rough (open) surfaces.

Example 7

Biocompatibility is an important concern when developing an implantabletherapeutic. In order to assess cytotoxicity of the polymer, the baremetal flats or flats coated with polymer only were incubated withvascular smooth muscle cells (VSMC) for 48 hours. During the experiment,the flats were separated from the cells using a 0.4 μm semi-permeabletranswell insert. To assess cytotoxicity, medium collected after thisincubation was assayed for lactate dehydrogenase (LDH), a known markerfor cytotoxicity, as LDH is released from the cell when it becomesinjured or “leaky.” Neither bare metal flats nor flats coated withpolyisobutylene-polystyrene triblock copolymer of either morphology hadany effect on LDH release compared to VSMC incubated without flats (FIG.15). Thus, this preliminary experiment suggests that the polymer-coatedflats exhibit no cytoxicity to VSMC.

While platelet activation is also an important factor in restenosis,polymers that promote platelet activation would likewise be undesirablefor use in a drug eluting stent. To test the effects of thepolymer-coated flats on platelet activation, bare metal flats coatedwith polyisobutylene-polystyrene triblock copolymer using a closedcompared to an open morphology were incubated for 48 h in medium.Platelets were then isolated from healthy, male donors and wereincubated with the resulting conditioned medium. Platelet activation wasassessed as platelet-derived growth factor (PDGF) release in either abasal (FIG. 16 a) or ADP-stimulated (FIG. 16 b) condition. Resultsindicated no significant effects of the polyisobutylene-polystyrenetriblock copolymer coated flats of either morphology.

Example 8

Another major goal in the development of a drug-eluting polymer is toensure that the system can release an adequate amount of drug to inhibitlocal smooth muscle cell proliferation. The polyisobutylene-polystyrenetriblock copolymers coated flats containing resveratrol or quercetinwere incubated in semi-permeable transwell inserts in plates containingVSMC. After 48 hours of drug elution, resveratrol coated in a smooth(closed) matrix polyisobutylene-polystyrene triblock copolymersignificantly inhibited proliferation at the 100 μg/cm² loadingconcentration. Quercetin significantly inhibited proliferation in flatscoated at 75 μg/cm², in either the particulate (open) or the smooth(closed) polyisobutylene-polystyrene triblock copolymer matrices. Datasupporting these results are shown in FIG. 17.

Determination of resveratrol release was performed using reversed phasehigh performance liquid chromatography (HPLC) coupled to a 4-channelCoularray electrochemical detector run at 590, 660, 730, and 800 mV.Results indicate that resveratrol release from the 100 mg/cm² coatedflat was approximately 4-fold greater than from the 50 mg/cm²-coatedflat, regardless of the morphology (FIG. 18). Slight, thoughinsignificant effects of the morphology on drug release were observed,with the closed matrix trending toward a greater release profilecompared to the open matrix. Importantly, the flats eluted lowmicromolar concentrations of resveratrol that are in a range thatexhibits efficacy in our in vitro tests. Also important is that at 28days, only 5-10% of the total drug loaded onto the flats had eluted,suggesting that in stents coating in a similar manner, sufficient drugshould remain in the coating to achieve efficacy over several monthsafter stent placement. Polymer deposition via the ElectroNanospray™process creates a textured surface with no noticeable defects or voids.This texture provides high surface area for the biostable polymer to bein contact with the surrounding environment. This is important becauseexposure to new drug-containing polymer through degradation does notoccur in this system as it would with biodegradable polymers.Cytotoxicity and proliferation data on the polymer-only samples provideevidence that the polyisobutylene-polystyrene triblock copolymer isbiocompatible. Establishing biocompatibility is a critical step in thedevelopment of the stent models. Proliferation data from drug-containingpolyisobutylene-polystyrene triblock copolymer (FIG. 17) suggests thatquercetin is releasing faster than resveratrol from the polymer withinthe first 48 hours.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. An implantable medical device, comprising: anexpandable balloon catheter having an outer surface; and an adherentlayer on the balloon catheter comprising a composite of polymer and afirst active agent selected from a group consisting of resveratrol,pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable derivatives thereof, and a second active agent selected froma group consisting of quercetin, pharmaceutically acceptable saltsthereof, and pharmaceutically acceptable derivatives thereof, whereinthe first and second active agents are dispersed within the polymer,wherein a concentration of the first active agent based on a surfacearea of the balloon catheter ranges from about 1 to about 5 μg/mm², anda concentration of the second active agent based on the surface area ofthe balloon catheter ranges from about 1 to about 5 μg/mm², and furtherwherein the composite includes a plurality of layers.
 2. The device ofclaim 1, wherein the polymer is biodegradable.
 3. The device of claim 1,wherein the polymer is a bioabsorbable polymer.
 4. The device of claim 1wherein the polymer is selected from a group consisting ofpolystyrene-polyisobutylene block copolymers, polyethyleneterephthalate, poly(lactide), poly(lactide-co-glycolide),poly(caprolactone), poly(lactide-co-caprolactone),poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),poly(ethylene-co-vinyl acetate), poly(vinylidenefluoride-co-hexafluoropropene), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, polyurethanes, desaminotyrosinepolyarylate, parylenes [polyxylylenes], polyphosphazene polymers,fluoropolymers, polyamides, isoolefin homopolymers and copolymers, vinylhomopolymers and copolymers, acrylate homopolymers and copolymers,methacrylate homopolymers and copolymers, polyethers, polyesters,polycarbonates and copolymers, polyethylene oxides, poly(ethyleneglycol) and derivatives, carbo-films, self-assembling polymer films andliposomes cellulosics, chondroitin-sulfate, gelatin, amino acid-basedpolymers, fibrin, chitin, extracellular matrix proteins, heparinizedcoatings, phospholipid liposomes and self-assembled arrays,poly-lactides and mixtures thereof.
 5. The device according to claim 1,wherein the first active agent is resveratrol and the second activeagent is quercetin, and further wherein a ratio of a weight ofresveratrol to a weight of quercetin is in a range selected from a groupconsisting of about 1:5, about 1:2, and about 1:1.
 6. The deviceaccording to claim 1, wherein a weight of the first active agent and aweight of the second active agent are in a ratio which is selected froma group consisting of about 1:1, about 1:2, about 2:1, about 1:2.5,about 2.5:1, about 1:4, about 4:1, about 1:5, about 5:1, about 1:10,about 10:1, about 1:20, about 20:1, about 1:25, about 25:1, about 1:50,about 50:1, about 1:100, about 100:1, about 1:200, about 200:1, about1:250, about 250:1, about 1:500, and about 500:1.
 7. The deviceaccording to claim 1, wherein a first weight comprises a weight of thefirst and second active agents; and a second weight comprises a weightof the polymer; and the first weight and the second weight are in aratio of the first and second active agents to the polymer is in a rangeselected from a group consisting of about 1:1, about 1:2, about 2:1,about 1:2.5, about 2.5:1, about 1:4, about 4:1, about 1:5, about 5:1,about 1:10, about 10:1, about 1:20, about 20:1, about 1:25, about 25:1,about 1:50, about 50:1, about 1:100, about 100:1, about 1:200, about200:1, about 1:250, about 250:1, about 1:500, and about 500:1.
 8. Thedevice according to claim 7, wherein the ratio is varied in some of thelayers.
 9. The device of claim 1, wherein each of the active agents mayhave different release profiles.
 10. The device of claim 1, wherein arelease profile of the active agents may be selected between rapid anddelayed.
 11. The device of claim 1, wherein a rapid profile coatingreleases at least one of the active agents substantially within one to afew hours.
 12. The device of claim 1, wherein a delayed profile coatingreleases at least one of the active agents over a period of at least onemonth, at least two months, at least six months, or at least one year.